In mammals, the unique tight junctions of urinary bladder surface epithelial cells are the fundamental mechanism by which the urinary bladder maintains it impermeability. However, the glycosaminoglycan layer on the luminal surface of the urinary bladder wall may be an important defense mechanism for protecting the transitional epithelium from urinary irritants (Chelsky, M. et al. 1994. Journal of Urology, 151:346). This glycosaminoglycan layer consists of mucopolysaccharides attached to a core protein that, in turn, is bound to a central hyaluronic acid string. This highly viscous, highly hydrophilic glycosaminoglycan layer may protect the transitional epithelium of the urinary bladder from irritants in the urine including, but not limited to, pathogens, microcrystals, proteins, calcium and carcinogens (Nickel, J. C. et al. 1993. Journal of Urology, 149:716). This glycosaminoglycan layer also may prevent small, uncharged molecules such as urea from diffusing to and across the transitional cell epithelium. Thus, the glycosaminoglycan layer lining the urinary bladder may act as a barrier between the environment within the lumen of the urinary bladder, and the transitional epithelium of the urinary bladder and may protect this transitional epithelium from inflammation, infection, trauma, stone formation and carcinogenesis.
Interstitial cystitis is a poorly understood bladder condition for which there is no universal effective treatment program (Fleischmann, J. D. et al. 1991. Journal of Urology, 146:1235). Symptoms include urgency for urination, increased frequency of urination and suprapubic pain usually relieved by voiding. Other symptoms include arthritis, spastic colon and low grade fever. Individuals with interstitial cystitis can be significantly disabled, and individuals with advanced interstitial cystitis can require major surgery in order to function. Although the etiology of interstitial cystitis remains unexplained, it has been suggested that abnormalities of or deficiencies in the glycosaminoglycan layer lining the transitional epithelium of the bladder may be a primary defect. (Eldrup J. 1983. British Journal of Urology, 55:488). These abnormalities or deficiencies may enable increased permeability of the transitional epithelium (Parsons, E. L. et al. 1990. Journal of Urology, 143:690) and this increased permeability may enable urinary solutes to gain access to the subepithelial tissue and to induce an irritative, inflammatory response that contributes to the symptoms of interstitial cystitis.
There is no standard treatment for interstitial cystitis. Among the treatments used are hydraulic distention of the urinary bladder, oral amitriptyline or sodium pentosanpolysulfate, intravesical instillation of dimethylsulfoxide, oxychlorosene sodium, silver nitrate, heparin, or a composition comprising an angiostatic steroid and pentosanpolysulfate. However, the efficacy of these treatments is variable.
Hydraulic distention of the urinary bladder is done under general or spinal anesthesia for one to two minutes at a pressure of 80 to 100 cm H.sub.2 O. In one study using hydraulic distention of the urinary bladder to treat interstitial cystitis, less than 55% of the patients treated reported relief immediately after treatment and only 2% reported relief six months after treatment (Hanno P. M. et al. 1991. Semin Urology, 9:143)
Instillation of dimethylsulfoxide (DMSO) into the urinary bladder for six to eight weeks resulted in a 53% response rate to DMSO versus an 18% response rate to placebo, with the average length of response being six months (Perez-Marrero, R. et al. 1967. Journal of Urology, 98:671). Pharmacological effects of DMSO include membrane penetration, enhanced drug absorption, anti-inflammatory and analgesic effects, collagen dissolution, muscle relaxation and mast cell histamine release. Side effects include increased vesical irritability and garlic-like breath odor. Equivalent results to instillation of DMSO have been reported with oxychlorosene sodium (Messing, E. M. et al. 1978. Urology, 12:381). However instillation of oxychlorosene sodium requires anesthesia because of intense discomfort.
Sodium pentosanpolysulfate is a low molecular weight synthetic glycosaminoglycan (U.S. Pat. No. 4,524,066 to Wolf) and is characterized by very low viscosity and high electronegativity.
U.S. Pat. No. 4,820,693 to Gillespie (Gillespie '693) discloses a composition and method for arresting angiogenesis and cell, capillary or membrane leakage comprising either oral or intravesical administration of an angiostatic steroid and pentosanpolysulfate. The molecular weight of pentosanpolysulfate is between 1.5.times.10.sup.3 and 5.times.10.sup.3 Daltons (The Merck Index, 11th Edition. 1989. p. 7093 at 7090). The molecular weight of the pentosanpolysulfate claimed in Gillespie '693 is between 1.6.times.10.sup.3 and 6.times.10.sup.3 Daltons, and is preferably about 2.times.10.sup.3 Daltons. U.S. Pat. No. 4,966,890 to Gillespie (Gillespie '890) discloses a composition and method for treating interstitial cystitis comprising either oral or intravesical administration of an angiostatic steroid and pentosanpolysulfate. Gillespie '890 teaches that pentosanpoiysulfate can be used in place of heparin and that pentosanpolysulfate, in combination with an angiostatic steroid, cures interstitial cystitis by arresting angiogenesis, cell membrane leakage and capillary leakage or exchange in the urinary bladder.
U.S. Pat. No. 5,180,715 to Parsons (Parsons '715) also discloses the use of pentosanpolysulfate for treating interstitial cystitis. Parsons '715 provides data to show that oral pentosanpolysulfate at doses in excess of 100 mg per day are most effective for treating interstitial cystitis. Parsons '715 also suggests, but provides no data to show, that intravesical instillation of pentosanpolysulfate is useful for treating interstitial cystitis. Parsons '715 teaches that pentosanpolysulfate can be used in place of heparin and that pentosanpolysulfate acts to block bacterial adherence to the transitional epithelium of the urinary bladder.
Pentosanpolysulfate as disclosed in Gillespie '693, in Gillespie '890 and in Parsons '715 is a low viscosity glycosaminoglycan. As interstitial cystitis may be related to a defect in the high viscosity glycosaminoglycan layer on the luminal surface of the bladder, intravesical administration of the low viscosity pentosanpolysulfate does not provide adequate protection to the transitional epithelium of the urinary bladder and associated structures. Therefore, what is needed is a substance which will coat the transitional epithelium of the urinary bladder and associated structures and provide a barrier between irritants within the lumen of the urinary bladder and associated structures and the transitional epithelium lining the urinary bladder and associated structures.
Hyaluronic acid (HA) is a heteropolysaccharide consisting of alternating residues of D-glucuronic acid and N-acetylglucosamine. HA is a linear polymer with a molecular weight of up to 13.times.10.sup.6 Daltons. It is found in connective tissue, in joint synovial fluid, in ocular vitreous humor, in umbilical cord, in cocks comb and is synthesized by some bacteria including, but not limited to streptococcal species. High molecular weight HA inhibits lymphocyte migration ((Balazs E. A. et al. 1973. In: Biology of Fibroblasts. Academic Press. pp. 237-252). The phagocytic and chemotactic capacities of neutrophils and leukocytes are also inhibited. (Brandt, K. D. 1974. Clinical Chemical Acta 55:307).
HA is highly viscous, highly electronegative and highly hydrophilic. The instillation of HA having an average molecular weight of not less than 2.times.10.sup.5 Daltons directly into the urinary bladder and associated structures to treat interstitial cystitis in the present invention provides unexpectedly excellent results in treating interstitial cystitis in a mammal with interstitial cystitis.